The neuroprotective effects of FG-4592, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, against oxidative stress induced by alpha-synuclein in N2a cells.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 09 2023
20 09 2023
Historique:
received:
14
03
2023
accepted:
15
09
2023
medline:
22
9
2023
pubmed:
21
9
2023
entrez:
21
9
2023
Statut:
epublish
Résumé
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The pathological hallmark of PD is the appearance of intraneuronal cytoplasmic α-synuclein (α-Syn) aggregation, called Lewy bodies. α-Syn aggregation is deeply involved in the pathogenesis of PD. Oxidative stress is also associated with the progression of PD. In the present study, to investigate whether a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitor, FG-4592 (also called roxadustat), has neuroprotective effects against α-Syn-induced neurotoxicity, we employed a novel α-Syn stably expressing cell line (named α-Syn-N2a cells) utilizing a piggyBac transposon system. In α-Syn-N2a cells, oxidative stress and cell death were induced by α-Syn, and FG-4592 showed significant protection against this neurotoxicity. However, FG-4592 did not affect α-Syn protein levels. FG-4592 triggered heme oxygenase-1 (HO-1) expression downstream of HIF-1α in a concentration-dependent manner. In addition, FG-4592 decreased the production of reactive oxygen species possibly via the activation of HO-1 and subsequently suppressed α-Syn-induced neurotoxicity. Moreover, FG-4592 regulated mitochondrial biogenesis and respiration via the induction of the peroxisome proliferator-activated receptor-γ coactivator-1α. As FG-4592 has various neuroprotective effects against α-Syn and is involved in drug repositioning, it may have novel therapeutic potential for PD.
Identifiants
pubmed: 37731009
doi: 10.1038/s41598-023-42903-7
pii: 10.1038/s41598-023-42903-7
pmc: PMC10511692
doi:
Substances chimiques
Prolyl Hydroxylases
EC 1.14.11.-
alpha-Synuclein
0
Neuroprotective Agents
0
Prolyl-Hydroxylase Inhibitors
0
Procollagen-Proline Dioxygenase
EC 1.14.11.2
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15629Informations de copyright
© 2023. Springer Nature Limited.
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